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. 2013 May 23;121(21):4377-87.
doi: 10.1182/blood-2012-12-474387. Epub 2013 Mar 12.

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

Satoshi Saida  1 , Ken-ichiro Watanabe, Aiko Sato-Otsubo, Kiminori Terui, Kenichi Yoshida, Yusuke Okuno, Tsutomu Toki, RuNan Wang, Yuichi Shiraishi, Satoru Miyano, Itaru Kato, Tatsuya Morishima, Hisanori Fujino, Katsutsugu Umeda, Hidefumi Hiramatsu, Souichi Adachi, Etsuro Ito, Seishi Ogawa, Mamoru Ito, Tatsutoshi Nakahata, Toshio Heike
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Free article

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

Satoshi Saida et al. Blood. .
Free article

Abstract

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

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